Annual Report 2022

Laboratory of Molecular Genetics

Haruna Takeda, Kotomi Sato

Introduction

 We have been conducting research using transposon-based in vivo screening in mice to elucidate the mechanism of colorectal cancer (CRC) progression and to explore therapeutic targets. We have focused on the fact that high-fat diet and chronic inflammation increase the risk of cancer development, and have created a novel mouse model of CRC. Tumors formed in these mice have been analyzed to comprehensively identify cancer-related genes. Currently, we are conducting detailed functional analysis of candidate genes in CRC development with the goal of identifying therapeutic targets.

 Mutations in genes that activate the Wnt pathway are frequently observed in CRC. To develop therapies targeting these genes, we are performing a comprehensive CRISPR screening using human CRC cell lines to identify therapeutic target genes and analyze their functions.

 We are working to elucidate the true nature of cancer and to identify therapeutic targets based on these genetic studies.

Research Activities

 We induced transposon-mediated mutations in a mouse model of colitis and obtained 229 tumors. We also obtained 86 tumors from non-inflammatory control mice. Genes that were significantly more frequently mutated in inflammation-associated tumors compared to non-inflammatory tumors were those involved in the cellular senescence and activin pathways. Detailed analysis revealed that TNFα, which is highly expressed in colitis tissues, induces cellular senescence pathway activation by altering the cellular state of colon epithelial cells. Cells with mutations in the cellular senescence pathway were shown to gain proliferative potential by TNFα, indicating that this may be a selective pressure for inflammation-related cancer development. Since mutations in cellular senescence pathway genes induce CDK4/6 activation, therapeutic experiments with CDK4/6 inhibitors in mice were conducted, showing that they may be effective in inflammation-associated colorectal cancer.

Education

 We accepted two undergraduate students from Kitasato University as trainees.

Future Prospects

 This year's study revealed that change in cellular state induced by chronic inflammatory stimuli is one of the molecular mechanisms that promote the formation of CRC. Since the mouse model of colitis-associated cancer used in the analysis develops metastatic cancer at a frequency of 20%, the enhancement of inflammatory stimulus-induced cell plasticity during the metastatic process will be analyzed. This analysis will lead to the identification of therapeutic targets for high-grade CRC.